Haploinsufficiency of Dnmt1 impairs leukemia stem cell function through derepression of bivalent chromatin domains. Genes Dev 2012 Feb 15;26(4):344-9
Date
02/22/2012Pubmed ID
22345515Pubmed Central ID
PMC3289882DOI
10.1101/gad.184341.111Scopus ID
2-s2.0-84863176405 (requires institutional sign-in at Scopus site) 123 CitationsAbstract
Epigenetic mechanisms regulating leukemia stem cells (LSCs) are an attractive target for therapy of blood cancers. Here, we report that conditional knockout of the DNA methyltransferase Dnmt1 blocked development of leukemia, and haploinsufficiency of Dnmt1 was sufficient to delay progression of leukemogenesis and impair LSC self-renewal without altering normal hematopoiesis. Haploinsufficiency of Dnmt1 resulted in tumor suppressor gene derepression associated with reduced DNA methylation and bivalent chromatin marks. These results suggest that LSCs depend on not only active expression of leukemogenic programs, but also DNA methylation-mediated silencing of bivalent domains to enforce transcriptional repression.
Author List
Trowbridge JJ, Sinha AU, Zhu N, Li M, Armstrong SA, Orkin SHMESH terms used to index this publication - Major topics in bold
AnimalsChromatin
DNA (Cytosine-5-)-Methyltransferases
DNA Methylation
Gene Expression Regulation, Neoplastic
Gene Knockout Techniques
Haploinsufficiency
Kaplan-Meier Estimate
Leukemia
Mice
Neoplastic Stem Cells
Tumor Suppressor Proteins
